MP-453085-1 CALORIC RESTRICTION ATTENUATES SINOATRIAL NODE AND ATRIAL ARRHYTHMOGENESIS IN AGED AND FRAIL MICE

Abstract

Atrial fibrillation (AF) and sinoatrial node (SAN) dysfunction are highly prevalent in elderly individuals; however, aging is also highly heterogenous. This heterogeneity has led to the concept of ‘frailty’, a state of increased vulnerability to adverse health outcomes in aging. Mild caloric restriction (CR; reducing caloric intake without malnutrition) can preserve cardiac function and improve frailty (healthspan); however, the effects of late-onset CR on SAN/atrial function in aging mice are unknown. To determine if CR affects frailty and SAN/atrial structure, function and arrhythmogenesis in aging mice. At 56 weeks of age, C57BL/6 mice were placed on either 25% CR or control diet ad libitum. Frailty scores were measured every 4 weeks for 24 weeks, at which point atrial and SAN function was studied using intracardiac electrophysiology, optical mapping, and histology. Young control mice (12 weeks) were used to account for differences in aging. Following 24 weeks of 25% CR, mice exhibited reduced frailty scores compared to the aged control diet (0.207±0.006 vs. 0.273±0.007, n=17-23; P<0.0001). Aged CR mice demonstrated lower AF inducibility (5/16, 31% vs. 12/18, 67%; P<0.05) compared to aged controls, as well as reduced corrected SAN recovery times (27.3±4.5 vs. 42.2±7.1, n=8-15; P<0.05). SAN recovery times in aged CR mice were similar to young mice (27.3±4.5 vs. 24.2.3±6.9, n=13-15; P>0.05). Due to substantial heterogeneity within groups, no difference in P-wave duration (PWD) was observed between groups. However, PWD (R2=0.15, P<0.01) and SAN recovery time (R2=0.19, P<0.0001) were each correlated with FI such that these fell along a continuum regardless of age or diet. Atrial conduction velocities were increased in CR mice compared to aged controls (51.1±2.4 vs. 19.2±2.7, n=5-7; P<0.0001), comparable to young controls (51.1±2.4 vs. 46.3±1.8, n=6-7; P>0.05). Atrial interstitial fibrosis was decreased in aged CR mice compared to aged controls (7.9±0.6 vs. 13.0±2.1, n=3; P<0.05), again comparable to young mice (7.9±0.6 vs. 5.0±0.2, n=3; P>0.05). Both conduction velocity (R2=0.32; P<0.01) and atrial fibrosis (R2=0.81; P<0.0001) showed a strong correlation to frailty score regardless of age or diet. Late-onset CR reduces frailty, improves SAN and atrial structure/function, and attenuates arrhythmogenesis in aging mice. These changes were strongly correlated, and often better predicted, by frailty compared to chronological age.